BackgroundGermline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is ...recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.MethodsPsychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks’ follow-up.ResultsWB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.ConclusionWB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
BackgroundCaring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (ie, deletions and duplications of genetic material) can place a considerable burden on parents and their ...quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared with the frequency of psychiatric problems in age-matched mothers from a large community study.MethodsCase–control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2680 age-matched mothers taking part in the Avon Longitudinal Study of Parents and Children study.ResultsMothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared with the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, we found that the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared with mothers from the community sample (30%, p=0.03).ConclusionOur study highlights the need for healthcare providers to devise treatment plans that not only focus on meeting the child’s needs but also assess and, if needed, address the mental health needs of the parent.
Prostate Cancer Risk by BRCA2 Genomic Regions Nyberg, Tommy; Frost, Debra; Barrowdale, Daniel ...
European urology,
October 2020, 2020-10-00, 20201001, Letnik:
78, Številka:
4
Journal Article
Recenzirano
Odprti dostop
A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3′) wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the ...BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval CI 4.46–15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97–5.57; hazard ratio = 2.34, 95% CI 1.09–5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23–72%) by the age of 75 yr and 78% (95% CI 54–94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort.
In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.
BRCA2 pathogenic variants located in a recently proposed prostate cancer cluster region confers higher risks of prostate cancer than other BRCA2 variants. This report corroborates the existence of this prostate cancer cluster region in a large prospective cohort study.
The National Institute of health and Care Excellence issued guidelines on familial breast cancer screening in 2004. Such guidelines should be uniformly implemented to ensure that members of the same ...family with the same level of risk, but living in different areas, have the same access to screening. We assessed uptake by creating a short, six question online survey designed to assess compliance in each regional area. We used this to conduct a survey of all 22 regional genetics services. There was a 100% response to the survey allowing a complete map to be created. The devolved nations had near complete compliance with the sole exception of SW Scotland, but in England the picture was fragmented with regions representing a combined population of 26.6 million (48%) not implementing the full NICE recommendations. Fifteen years after the publication of the original guidelines, major inequity in provision for screening still occurs and a postcode lottery exists for the management of women from families with a history of breast cancer. We estimate that up to 73 preventable breast cancer deaths occur each year due to the current inequity of access. It may be time to consider alternative funding and implementation models to ensure consistent access across the country.
To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability ...of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design.
Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop.
Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability.
A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.
The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (
BRCA1/2
) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian ...Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at
BRCA2
(47/98),
BRCA1
(24/98),
PALB2
(8/51),
ATM
(7/51),
CHEK2
(6/51)
MSH6
, (2/51),
RAD51C
(2/51) and
TP53
(2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for
BRCA1
and
MSH6
pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for
BRCA2
and
BRCA1
pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (
p
= 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from
BRCA1
and
BRCA2
, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for
BRCA1/2
between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.
BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) ...in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives.
We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs).
A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9–15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2–2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62–1.40) in the overall cohort, 0.85 (95% CI 0.48–1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57–1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20–3.17) in the overall cohort.
Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.
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